Salicylic Acid Derivatives Research Articles

Interaction of Salicylamide and Salicylic Acid with Iron and Cobalt and their Comparative Study by IR and NMR

The complexes formed by salicylic acid and several substituted derivatives of salicylic acid (Salicylamide) with essential metal ions of the soil (iron and cobalt) have been investigated at 25° and in a medium of variable ionic strength using pH. The equilibrium constants of complex formation of the 1 : 1 , 1 : 2 and1 : 3 mole ratio metal–acid complexes formed are discussed with reference to the activity degradation of substituents. Salicylic acid and Salicylamide after disposal can also react with the various metal ions present in the soil to form complexes. The rate at which these complexes are formed is done with the help of UV-vis. Spectroscopy. The complexes formed are characterized by various Spectroscopic technique viz. FTIR and NMR.

Synthesis and in vitro evaluation of triphenylphosphonium derivatives of acetylsalicylic and salicylic acids: structure-dependent interactions with cancer cells, bacteria, and mitochondria

Salicylic acid (SA) remains one of the most fruitful natural compounds to generate drug molecules with versatile activities. In this study, effective synthesis of SA and acetylsalicylic acid (ASA) derivatives with a carrier triphenylphoshonium (TPP) group was proposed. A series of SA and ASA conjugates linked with the TPP group via alkyl chain linker (C3-C10) was synthesized. The conjugates showed enhanced TPP-mediated cytotoxicity towards MCF-7, Caco-2, PC-3 cells in proportion to the linker length. 7e, 8e (C9), and 7f (C10) were the most active against the cancer cells with IC50 = 0.6–1.9 µM while were less toxic for HSF. Similarly, antibacterial (bactericidal) activity of the compounds against S. aureus increased with the linker elongation. The lowest MIC for SA and ASA derivatives were 4 and 1 µM, respectively. The TPP conjugates induced early linker length-dependent mitochondria depolarization and concurrent superoxide radical production in the cancer cells. The most lipophilic conjugates were found to specifically interact with ROS probe 2′,7′-dichlorofluorescin diacetate, forming mixed aggregates with the probe and inhibiting its fluorescence upon oxidation. These interactions were exploited to probe the compounds inside living cells. The results identify 7e and 7f as promising mitochondria-modulating and anticancer agents with increased cellular availability.

Iridium-catalyzed intramolecular asymmetric allylic etherification of salicylic acid derivatives with chiral-bridged biphenyl phosphoramidite ligands

Iridium-catalyzed intramolecular asymmetric allylic etherification of salicylic acid derivatives was successfully realized for the first time.

A new class of anionic metallohelicates based on salicylic and terephthalic acid units, accessible in solution and by mechanochemistry.

We present a new class of anionic metallohelicates based on an abundant, industrially relevant salicylic acid derivative, leading to discrete double and triple-stranded architectures based on divalent and trivalent metals (Cu2+, Fe3+, respectively). The ability to assemble the metallohelicates in a solvent-free environment presents the opportunity to develop an inexpensive and environmentally-friendly design of helicate materials.

Effect of Foliar Applied Acetylsalicilic Acid on Wheat (Triticum aestivum L.) under Field Conditions

The exogenous application of salicylic acid prevents plant damage caused by various abiotic stresses (drought, high and low temperatures, salinity) and helps plants to build resistance to biotic stresses (pathogens). Acetylsalicylic acid, which is a synthetic salicylic acid derivative, has the same properties. In the face of climate change and a greater likelihood of extreme weather events, the use of these acids can significantly help to ensure proper growth and development of plants, especially sensitive species, even under stress conditions. The problem, however, is choosing the right dose (concentration) and time of application, and individual species sensitivity. The aim of the study was to assess the effect of acetylsalicylic acid on the growth and yield parameters of spring wheat. A field trial was carried out in 2013 and 2014 at the Institute of Plant Protection—National Research Institute in Poznan (Poland). The experiment was established on spring wheat cv. ‘Tybalt’, in four replications. Acetylsalicylic acid was tested in two concentrations: 0.3 and 0.5 mM. Each concentration was applied to the crop twice at growth stage BBCH 29 (end of tillering) and 7 days afterwards, and at growth stage BBCH 37 (flag leaf just visible) and 7 days afterwards. The study evaluated 12 traits of the crop, including plant height, chlorophyll content in the flag leaf, length of the ear, and quality and quantity parameters of the yield. The study showed that both the selection of the appropriate concentration and the time of acetylsalicylic acid application have a significant impact on the growth and development of the wheat. The acetylsalicylic acid increased the amount of chlorophyll in the leaves, the number of grains in the ear, the mass of a thousand grains, and grain yield. The present study did not confirm significant differences between the acetylsalicylic acid concentrations. The concentration of 0.5 mM proved more effective only for such traits as plant height and protein content in the grain. The study showed that it is not the concentration but the time of acetylsalicylic acid application that is more important for the growth of the wheat. Although there were no significant differences between the effects of earlier and later application time on plant height or chlorophyll content, most of the structural and qualitative parameters of the yield (number of grains in the ear, grain density, grain hardness, protein, gluten and starch content) were better after later application of acetylsalicylic acid (GS BBCH 37).

Non-steroidal Anti-inflammatory Drugs Target TWISTED DWARF1-Regulated Actin Dynamics and Auxin Transport-Mediated Plant Development

The widely used non-steroidal anti-inflammatory drugs (NSAIDs) are derivatives of the phytohormone salicylic acid (SA). SA is well known to regulate plant immunity and development, whereas there have been few reports focusing on the effects of NSAIDs in plants. Our studies here reveal that NSAIDs exhibit largely overlapping physiological activities to SA in the model plant Arabidopsis. NSAID treatments lead to shorter and agravitropic primary roots and inhibited lateral root organogenesis. Notably, in addition to the SA-like action, which in roots involves binding to the protein phosphatase 2A (PP2A), NSAIDs also exhibit PP2A-independent effects. Cell biological and biochemical analyses reveal that many NSAIDs bind directly to and inhibit the chaperone activity of TWISTED DWARF1, thereby regulating actin cytoskeleton dynamics and subsequent endosomal trafficking. Our findings uncover an unexpected bioactivity of human pharmaceuticals in plants and provide insights into the molecular mechanism underlying the cellular action of this class of anti-inflammatory compounds.

Novel 2-Aryloxazoline Compounds Exhibit an Inhibitory Effect on Candida spp., Including Antifungal-Resistant Isolates.

Because of the increased resistance to currently available antifungals, fungal infections represent a significant challenge to human health. Herein, we report the synthesis of 2-aryloxazoline derivatives from the reaction between l-threonine and derivatives of salicylic or naphthoic acid. In total, 26 compounds were obtained and tested against species of Candida, Cryptococcus, and Aspergillus. We found that all of the compounds inhibited the growth of Candida species at low concentrations (<0.25 μg/mL) and exhibited reduced hemolytic and cytotoxic activities. Additionally, compounds 4i and 9i were especially effective against antifungal-resistant isolates and the emerging fungus Candida auris. However, the compounds were less active on Cryptococcus and Aspergillus. Because of the improved in vitro antifungal efficacy and attenuated cytotoxicity, these two 2-aryloxazolines obtained from salicylic and naphthoic acid derivatives, respectively, may be considered lead molecules for the development of novel antifungal drugs.

Synthesis of acyclic and cyclic phosphonates based on substituted 2-hydroxybenzylic alcohols

A convenient synthesis of benzylic phosphonates and 2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxides substituted at the aromatic ring, as well as their precursors, 2-hydroxybenzylic alcohols, from the derivatives of salicylic aldehyde, salicylic acid, and 2-hydroxyacetophenone bearing an additional hydroxy or methoxy group at the para position of the aromatic ring was developed. For the first time, the possibility of selective demethylation of the methoxy group positioned ortho to the methylene phosphonate fragment with retention of the methoxy group at the para position was shown.

Identification and Quantification of a Phytotoxic Metabolite from Alternaria dauci.

Alternaria dauci is the causal agent of Alternaria leaf blight (ALB) in carrot (Daucus carota) crops around the world. However, to date, A. dauci has received limited attention in its production of phytotoxic metabolites. In this investigation, the bioassay-guided isolation of the extract from liquid cultures of A. dauci resulted in the isolation of two metabolites identified as α-acetylorcinol (1) and p-hydroxybenzoic acid (2), based on their spectroscopic data and results from chemical correlation reactions. Testing of both metabolites in different assays showed an important phytotoxic activity for p-hydroxybenzoic acid (2) when tested in the leaf-spot assay on parsley (Petroselinum crispum), in the leaf infiltration assay on tobacco (Nicotiana alata) and marigold (Tagetes erecta), and in the immersion assay on parsley and parsnip (Pastinaca sativa) leaves. Quantification of the two metabolites in the crude extract of A. dauci kept at different times showed that p-hydroxybenzoic acid (2) is one of the first metabolites to be synthesized by the pathogen, suggesting that this salicylic acid derivative could play an important role in the pathogenicity of the fungus.

The Influence of Inducing Agents Applied by Soil Drenches on Disease Severity of Apple and Pear Scab

Apple and pear scab are foliar diseases of ornamental and fruiting apple and pear trees. Unmanaged, yield and aesthetic losses can be severe. Overreliance on synthetic fungicides means novel means of disease management are required. Field trials were conducted using apple (Malus cv. Crown Gold) and pear (Pyrus communis ‘Williams Bon Chrétien’) to assess the efficacy of a range of commercially available inducing resistance (IR) agents (harpin protein, potassium phosphite, salicylic acid derivative, and chitosan) as root drenches against both scab diseases. A synthetic fungicide (penconazole) spray program used within the UK for apple and pear scab control was included for comparison. Each IR agent was applied four times, (i) before the visible appearance of scab (April through June, i.e., preventatively) or (ii) after symptoms of scab were visibly observed (June through August, i.e., curatively). Limited efficacy as scab protectants was demonstrated when IR agents were applied curatively. Likewise, limited efficacy was recorded when IR agents were applied once or twice as a preventative measure. However, when IR agents were applied as root drenches greater or equal to three times, efficacy as scab protectants was confirmed (increased leaf chlorophyll content, increased fruit yield, reduced leaf and fruit scab severity). A synthetic fungicide penconazole spray program provided the greatest protection against apple and pear scab in all trials when sprayed preventatively rather than curatively. Results suggest application of at least three root drenches from April through June with an appropriate IR agent provides a useful addition to existing methods of apple and pear scab management under field conditions.

Synthesis, characterization and cytotoxic activity evaluation of 4-(1,2,3-triazol-1-yl) salicylic acid derivatives

A novel series of 4-(1,2,3-triazol-1-yl) salicylic acid derivatives was synthesized from 4-azidosalicylic acid and diverse alkynes using copper catalyzed azide-alkyne cycloaddition as key process and fully characterized by using different analytical techniques. The in vitro antiproliferative activity of these new compounds was explored against a series of tumoral cell lines which included U251 (human glioblastoma), PC-3 (human prostate cancer cell line), K562 (human leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma) and SKLU (human lung adenocarcinoma), showing selective activity in some compounds. Moreover, molecular docking studies suggest a strong interaction between ARG-154 in STAT3 and the triazole fragment which can explain the inhibitory activity observed in these compounds.

Isolation and characterization of secondary metabolites from Gaultheria tenuifolia berries.

Gaultheria berries (Ericaceae) are consumed as food or used in folk medicine throughout the world. In the present study, Gaultheria tenuifolia berries were studied to describe their polyphenol and iridoid composition, aroma volatiles, and cytoprotective effects. In total, 14 metabolites were isolated using a combination of countercurrent chromatography and Sephadex LH-20, namely, cyanidin-3-O-β-galactoside, cyanidin-3-O-β-arabinoside, 3-O-caffeoylquinic acid, 5-O-caffeoylshikimic acid, quercetin, quercetin-3-O-β-glucuronide, quercetin-3-O-β-rutinoside, quercetin-3-O-β-glucoside, quercetin-3-O-β-arabinoside, quercetin-3-O-β-rhamnoside, 6α-hydroxydihydromonotropein-10-trans-cinnamate, monotropein-10-trans-cinnamate, and an (epi)-catechin dimer and trimer. Other flavan-3-ols, proanthocyanidins, and iridoids were tentatively identified by spectroscopic and spectrometric means in the fruit extracts. The tentative volatile organic compound characterization pointed to methyl salicylate as responsible for the aroma of this species. The extracts showed significant cytoprotective effects in an oxidative stress model in human gastric epithelial cells. This is the first report on the isolation, characterization, and potential biological activity of secondary metabolites from G. tenuifolia berries and insights on its possible application as a functional food. PRACTICAL APPLICATION: Berries are desirable fruit species because of their phytochemical composition and pleasant taste. Gaultheria berries are special due to their high content of iridoids and the presence of salicylic acid derivatives. Aroma of native berries is relevant for the development of new products reflecting the local identity and use of fruits. The present work involves cooperation of academia and industry on the constituents of the native products. The results provided in this article could be useful for the introduction of this species in the food and nutraceutical industries.

Palladium-Catalyzed [5 + 1] Annulation of Salicylic Acid Derivatives and Propargylic Carbonates

Abstract A palladium-catalyzed annulation reaction between salicylic acid derivatives and propargylic carbonates via the cleavage of a propargylic carbon–oxygen bond is described. This rare annulation reaction uses propargylic compounds as the C1 component for heterocyclic products and can be applied to the preparation of unique five- or six-membered cyclic compounds. The corresponding products contain a fully substituted allylic carbon and the reaction is characterized by high functional-group tolerance.

Micelle-mediated extraction for speciation and spectrophotometric determination of iron using a newly synthesized salicylic acid derivative

A sensitive and selective method for speciation and determination of iron was developed using cloud point extraction combined with spectrophotometry. The method depends on formation of complex between Fe3+ and a newly synthesized reagent, 4-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)-2-hydroxybenzoic acid (DOPHHBA), and its extraction into Triton X-114 rich phase prior to spectrophotometric determination at 438 nm. Total Fe was determined as Fe3+ by the same methodology after oxidation of Fe2+. The method exhibited dynamic linear range from 4.0 to 500 µg L-1 with limit of detection and enrichment factor of 1.2 µg L-1 and 95.2, respectively. The accuracy of the method was tested by analysis of certified reference materials and spiked samples. The method was applied for speciation of Fe in natural water samples and determination of Fe in food samples with satisfying results. The analytical results are statistically comparable with those obtained by a standard ICP-OES method.

NSAIDs Target TWISTED DWARF1-Regulated Actin Dynamics and Auxin Transport-Mediated Plant Development

The widely used non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, are derivatives of the phytohormone salicylic acid (SA). In plants, SA is well-known to regulate immunity as well as development, whereas there was no study focusing on the effects and mechanism of action of NSAIDs in plants. Our studies here in the model plant Arabidopsis thaliana reveal that NSAIDs exhibit largely overlapping physiological activities to SA. NSAID treatments in Arabidopsis seedlings lead to shorter and agravitropic primary roots and inhibited lateral root organogenesis. Notably, in addition to the SA-like action, which in roots involves binding to the Protein Phosphatase 2A (PP2A), NSAIDs exhibit also PP2A-independent effects. Cell biological and biochemical analyses unravel that many NSAIDs bind directly to and inhibit the chaperone activity of the FKBP42, TWISTED DWARF1, thereby regulating the dynamics of actin cytoskeleton and subsequent endosomal trafficking. Our findings uncover an unexpected bioactivity of human pharmaceuticals in plants, and provide novel insights into the molecular mechanism underlying the cellular action of this class of anti-inflammatory compounds.

Bisthioureas of pimelic acid and 4-methylsalicylic acid derivatives as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP): Synthesis and molecular docking studies

Alkaline phosphatases (ALPs) are membrane bound metalloenzymes, distributed all over the body. Recent studies have revealed that by targeting ALPs can lead towards the treatment of many deadliest diseases including cardiac, cancerous and brain diseases. Thioureas and their derivatives are of considerable significance and are privileged scaffolds in medicinal chemistry. They show a wide range of pharmacological activities such as antibacterial, antiparasitic, anti-inflammatory and antioxidants etc. On the other hand, salicylic acid and its derivatives are known for its broad spectrum of activities. The work presented comprises of synthesis of N-acyl-N'-aryl substituted bisthioureas of pimelic acid (1–7) and 3,5-dimethyl pyrazole (11), 1-aroyl-3-aryl thiourea (12) and 1,3,4-oxadiazole (13) derivatives of 4-methyl salicylic acid. Structures of all the synthesized compounds were characterized by FT-IR and 1H NMR spectroscopic analysis. Synthesized compounds were evaluated for their alkaline phosphatases inhibition potential and exhibited high potency as well as selectivity towards h-TNAP and h-IAP. Compound 7 and 12 which were the bisthiourea derivative of pimmelic acid and thiourea derivative of 4-methyl salicylic acid, respectively, showed excellent selectivity against h-TNAP and h-IAP, respectively.

The Selectivity of Fosfosal for STAT5b over STAT5a is Mediated by Arg566 in the Linker Domain

Fosfosal is the O‐phosphorylated derivative of salicylic acid, with documented clinical use as a prodrug for the treatment of inflammatory diseases. We recently discovered that fosfosal itself inhibits the protein‐protein interaction domain, the SH2 domain, of the tumor‐related transcription factor STAT5b. Here, we demonstrate that fosfosal is selective for STAT5b over its close homologue STAT5a. This selectivity is mediated by the STAT5b residue Arg566, located in the SH2 domain‐adjacent linker domain. Our data provide further evidence for the role of the STAT linker domain in determining the activity of small molecules against the SH2 domain. We present a refined binding model for fosfosal and STAT5b, which can serve as the basis for the development of fosfosal‐based STAT5b inhibitors.

Scalable photoelectrochromic glass of high performance powered by ligand attached TiO2 photoactive layer

A scalable photoelectrochromic (PEC) glass which can be darkened on exposure to sunlight and return to its original clear state in the absence of sunlight without any expensive materials like ruthenium dye or transparent conductive oxide was fabricated. The PEC glass is composed of light absorbing layer of ligand attached titanium oxide, color changing layer of tungsten oxide and the electrolyte containing redox mediator. This work reports, for the first time, on an application of salicylic acid attached TiO2 photoactive layer for PEC devices. The applicability of various salicylic acid derivatives attached TiO2 films in PEC device is individually investigated in dye solar cells. Among various salicylic acid derivatives studied, 5-methylsalicylic acid showed the best performance in terms of charge generation for coloration of WO3. By using 5-methylsalicylic acid instead of ruthenium dye, lower cost, higher stability, and simpler electrolyte composition have been realized. The changes in transmittance for coloration (ΔTC) depend on the thickness of WO3 and TiO2 in this device. Thus, we changed the thickness of WO3 and TiO2 to get the highest variation of transmittance for coloration. The preliminary optimization of PEC device exhibits ΔTC of 40.8% at 550 nm, the wavelength most sensitive to the human eye, and of 64.3% at 700 nm.

Acetylsalicylic acid (ASA) induced fusarium rot resistance and suppressed neosolaniol production by elevation of ROS metabolism in muskmelon fruit

Major losses in the harvested muskmelon fruit can be attributed to decay fungi. Fusarium sulphureum is the major causal agent of fusarium rot in muskmelon, which in turn, not only causes quality deterioration but also leads to neosolaniol (NEO) contamination. Therefore, new strategies to manage muskmelon postharvest decay and decrease NEO production are of paramount importance. Acetylsalicylic acid (ASA), a derivative of salicylic acid (SA), is a putative endogenous signal molecular and can induce resistance against decay fungi in postharvest fruit and vegetable. To investigate the mechanism of induced resistance by ASA treatment against fusarium rot of muskmelon, the fruit was treated with ASA, followed by the inoculation with F. sulphureum. Results showed that the reduction of fusarium rot severity and the suppression of NEO accumulation were linked with the elevation of ROS metabolism. ASA treatment enhanced ROS accumulation and induced the enzymatic activities and up-regulated gene expressions involved in ROS metabolism. Taken together, the present study provides substantial evidence which ASA induced resistance against F. sulphureum in muskmelon fruit to control the fusarium rot development.

Binding mechanism, conformation, and stability of diflunisal and mycophenolic acid with p300 HAT enzyme using molecular dynamics simulation and binding free energy analysis

Among all posttranslational modifications in eukaryotic cell, acetylation is an important one it is controlled by histone acetyltransferase (HAT) enzyme. The aberrant function of this enzyme is forefront for the cause of several nefarious diseases like, cancer, neurological disorders, cardiovascular, and lung diseases. Reports outline that blocking the enzymatic action of this enzyme by an inhibitor molecule is the only remedy to cure these diseases. The in vitro analysis shows that highest inhibition rate of salicylic acid and its derivatives acetylsalicylic acid, 4-amino salicylic acid, diflunisal, mycophenolic acid, 5-amino salicylic acid, and repaglinide against p300. The in silico (molecular docking) analysis confirms that the diflunisal (−6.14 kcal/mol), mycophenolic acid (−6.86 kcal/mol), and repaglinide (−6.26 kcal/mol conformer-4) molecules give highest binding energy values compared with other salicylic acid derivatives and they form strong interactions (H-bond) with the Arg1410, Trp1436, Thr1411, Trp1466, and Tyr1467. These interactions stabilize the molecules in the active site; it leads to inhibit the histone acetylation. The mycophenolic acid is retained these key interactions with the active site amino acid residues (Cys1438, Tyr1446, and Tyr1467) compared with the diflunisal molecule in MD simulation; which is stable up to 40 ns. The binding free energy of mycophenolic acid (−26.26 kcal/mol) is relatively high on compared with the diflunisal (−7.86 kcal/mol).